Ferf-Butoxycarbonyl group

To avoid any loss of benzyl ester protection during acidolytic removal of the benzyloxy-carbonyl and ferf-butoxycarbonyl groups, electron-withdrawing substituents were used to destabilize the intermediate benzyl cation and thus to increase the acid stability. In addition to the very useful 4-nitrobenzyl esters (vide infra), the picolyl ester (see Section 2.2.1.2.2.3) as well as halo-P l or cyano-P°°l substituted benzyl esters have been reported, the latter being rarely used for a-carboxy protection. Conversely, an increase in sensitivity toward acids can be achieved by introduction of electron-releasing substituents, such as methoxy or methyl groups. Addition of scavengers to quench intermediate carbocations and to prevent electrophilic substitutions at sensitive amino acid side chains is beneficial in the deprotection of such esters. 

The synthesis of glycopeptides of L-asparagine by the solid-phase procedure required a derivative protected, for example, by the acid-labile N-(ferf-butoxycarbonyl) group. Thus, 1-benzyl N-(terf-butoxycarbonyl)-L-aspartate (88) was condensed with 2,3,4,6-tetra-0-acetyl-)3-D-gluco-pyranosylamine (2), or the 2-acetamido-2-deoxy analog 8, by the active ester method in the presence of DCC and 1-hydroxybenzotriazole, to give 89 and 90, respectively ... 

The same combination of reagents (TMSOTf/2,6-lutidine) has been employed to deprotect (V-ferf-butoxycarbonyl groups from substrates in the solid phase synthesis of several peptides, without cleaving the substrates from the support as would occur in the case of using TFA with TFA-sensitive resins (such as Rink s amide resin) (eq 100). This method has great potential for the solid-phase synthesis of small molecule libraries. Such a reagent combination had been previously developed for solution phase reactions of nonpeptidic substrates. ... 

In SPPS, there are two main protecting groups commonly used for Ai -protection [3] ferf-butoxycarbonyl (Boc) [7] and 9-fluorenylmethoxycarbonyl (Fmoc) [8] (Fig. 2). 

FIGURE 3.17 Reagents for protection of amino groups as the ferf-butoxycarbonyl derivatives. terf-Butyl chloroformate is rarely used because of its low boiling point. The oxime is 2-ferf-butoxycarbonyloximino-2-phenylacetonitrile,45 Boc20 = di-ferf-butyl dicarbonate, or di-terf-butyl pyrocarbonate.46 (Tarbell et al., 1972 Pozdvev, 1974). Acylations are carried out at pH 9 to avoid dimerization. 

When the ferf-butoxycarbonyl (Boc) carbamate-derived sulfone 5 was subjected to the Bi(OTf)34H20-catalyzed allylation conditions (Scheme 2), the cyclic carbamate 6 was obtained as the major product (36%, diastereoisomeric ratio (dr) = 82 18), along with the corresponding allylation product 7, although in low yield (16%). Such cyclic carbamate resulting from the internal capture of an intermediate (3-silyl cation with the Boc group and concomitant loss of isobutylene has already been reported in the literature [59]. 

Treatment of 4-methoxy-2-oxazolidinone 86 with indolylmagnesium bromide 87, followed by A-protection with a ferf-butoxycarbonyl (Boc) group affords NJd -di-Boc-4-(3-indolyl)-2-oxazolidinone 88. Subsequent treatment with A-bromosuc-cinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) followed by electrochemical reduction yields the protected 4-(3-indolyl)-2(3//)-oxazolone 90 (Fig. 5.23). The Boc groups are easily removed by pyrolysis."" "" ... 

As mentioned in Section 10.6.2, synthesis of 1-hydroxyethylene peptides can be initiated by adding a ferf-butoxycarbonyl N-protected a-amino aldehyde to an optically active Grignard reagent (Scheme 7)J11-13 This reaction affords a diastereomeric mixture of the C4 epimers of the hydroxy ether in good yields. In most cases the mixture is enriched in the 45-epimer and the epimers are readily separable. The yields and the ratios of the resulting 45- and 4R-epimers obtained from several examples of this reaction are summarized in Table 1. When this reaction was attempted with the aldehyde prepared from Aa,Ae-bis-tert-butoxycarbonyl-protected Lys, the desired product was not obtained. The anion of the Lys Ne-tert-butoxy-carbonylamino group probably reacts with the aldehyde to form a cyclic aminol that does not... 

At the start of the peptide synthesis, the C-terminal amino acid is bonded through its carboxyl group to the resin by a nucleophilic attack of the carboxy-late ion on the chloromethyl groups. The a-amino group must be suitably protected, as with ferf-butoxycarbonyl, before carrying out this step ... 

The selective cleavage of the IV-t-butoxycarbonyl group in the presence of TBDMS (t-butyldimethylsilyl) (selective only when the protected alcohol was phenolic) or TBDPS (ferf-butyldiphenylsilyl) (completely selective) ethers can be achieved68 using a saturated solution of HC1 in ethyl acetate. 

To exploit the reactions of the C-lithio derivatives of N-unsubstituted pyrroles and indoles, N-protecting/masking groups such as ferf-butoxycarbonyl, terZ-biitylcarbamoyl, benzenesulfonyl, dimethylamino, and dimethylaminomethyl must be used. This is illustrated by a route to G-acylated pyrroles 441. Another very useful process involves N-lithiation, N-carbonation, and lithiation of the resulting indol-l-ylcarboxylate at C(2) reaction with an electrophile and loss of carbon dioxide during work-up give N-unsubstituted 2-substituted indoles, for example, 2-haloindoles in excellent yields. 

B-Bromocatecholborane cleaves MEM and MOM ethers at comparable rates and fm-butoxycarbonyl, benzyloxycarbonyl, /erf-butyl ethers, benzyl ethers, and TBS ethers are usually compatible,462 but not always. At a late stage in Boger s synthesis of Vancomycin, a MEM group was cleaved from a complex, multifunctional intermediate, but an tf-ferf-butoxycarbonyl was also cleaved and had to be restored in a separate step.169... 

Vicinal diols in sugar substrates can also be protected as their 2-(ferf-butoxycarbonyl)-ethylidene ( Bocdene ) or 2-(methoxycarbonyl)-ethylidene ( Mocdene ) derivatives in the reaction with ferf-butyl or methyl propynoate. The acetal-like structures of these protecting groups is of interest because they are stable under acidic conditions, which allows their selective deprotection versus other acetals, and can be removed under basic conditions via an addition-elimination mechanism (O Scheme 21) [140]. The procedure is not suitable for 1,3-or 1,4 diols. 

Hydrogen bromide may be used to remove either the benzyloxycarbonyl or ferf-butoxycarbonyl protecting group. The benzyloxycarbonyl protecting group may also be removed by catalytic hydrogenolysis. 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

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